Dopamine receptors mediate signals that regulate neuronal function, and thereby have important roles in physiological processes governed by neuronal function. The absence of normal dopamine receptor expression, excessive expression of dopamine receptors or presence of dopamine receptors in abnormal locations can contribute to aberrant physiological processes, leading to disease, degeneration and other abnormal conditions. Accordingly, the amount or distribution of dopamine receptors in a cell, tissue or organ of an individual can be indicative of a variety of neurological disorders, including central nervous system and peripheral nervous system disorders.
Positron emission tomography (PET) is a high resolution, non-invasive imaging technique that utilizes molecules labeled with positron-emitting radioisotopes to visualize and measure rates of biochemical processes in tissues and cells of living subjects. Single-photon emission computed tomography (SPECT) is another radioisotope imaging modality with similar applications. Both are used in medical imaging of patients for diagnosing disease and monitoring treatment. Imaging of this type is typically done with non-specific compounds complexed with an appropriate positron emitting radionuclide. For example, the most commonly used radiotracer is 18F labeled 2-fluoro-2-deoxy-D-glucose (FDG) which is naturally absorbed by cells but cannot be metabolized. When administered, FDG accumulates in cells with a high metabolic rate, a fundamental characteristic of cancer cells. Though PET and SPECT are widely used, few specific radiotracers are readily available as for study of particular biological molecules relevant in medical conditions, such as dopamine receptors.
Owing to the importance of dopamine signaling in neuronal function, considerable effort has been devoted to developing imaging compounds specific for dopamine receptors. (R)-(−)-2-fluoro-N-propylnorapomorphine (1) is recognized as one of the most efficient and most selective D2 dopamine receptor agonists. Considerable effort has previously been devoted to the development of imaging compounds based on apomorphine derivatives (2-23). However, because of the strong ring activation, ring modification is strongly favored in the 2 position of the A ring. Amine, halogen and hydroxyl groups have been placed at this position with an N-n-propyl group and the molecule being otherwise unmodified. An exception to modification of the apomorphine at the 2 position is dibromination at the 8 and 9 positions of the D apomorphine ring (2). In light of the recent appreciation that apomorphine structure around the 1, 2 and 3 positions of the A apomorphine ring has significant effects on the specifics of dopamine receptor interaction, it would be of considerable value to develop a synthetic approach in compounds with a variety of substituents not only at the 1, 2 and 3 positions of the A ring, but also the 8 and 9 positions of the D ring. Thus, there exists a need for apomorphine-based imaging compounds and chemistries for the formation of such compounds so as to enhance neuronal function diagnosis.